Deep brain stimulation (DBS) of the subthalamic nuclei (STN) may provide substantial reduction of symptoms in people with Parkinson disease (PD) and DBS of the thalamic ventral intermediate nucleus (VIM) markedly reduces tremor in people with disorders such as essential tremor (ET). Increasing data also indicates that STN DBS in PD may produce unwanted cognitive impairments, such as impairments of spatial delayed recall or response inhibition. Despite these dramatic clinical effects, the precise mechanism of action of DBS remains unclear. Recent studies, including several from this lab, indicate that DBS produces a net increase in neuronal output from the site of stimulation either the STN in PD or VIM in ET, and there may be important differences in the effects of STN on the left and right sides of the brain. Nevertheless, how this action and its asymmetry provide clinical benefit while simultaneously interfering with selected cognitive function remains unknown. We hypothesize that STN and VIM DBS provide motor benefit by altering function of specific motor brain regions, whereas, STN DBS impairs cognitive skills by altering function of selected prefrontal regions. Further, we propose that there are substantial differences between left and right-sided STN stimulation on aspects of motor and cognitive function. We will test these specific hypotheses using PET to measure brain blood flow responses to varying levels of STN or VIM stimulation in people with PD or ET and then correlate these PET responses with cognitive or motor responses to DBS in the same subjects. These studies have the potential to reveal valuable insights into the mechanism of DBS and also into the pathophysiology of these diseases and their clinical manifestations. For example, we may identify specific brain pathways that mediate cognitive impairment from STN DBS that are distinct from those that mediate motor benefit. This could directly lead to designing new strategies to maximize motor benefit and minimize cognitive impairments. We also have the potential to provide a rationale for investigating new sites for DBS that may be more accessible than those currently used. This innovative study brings together rigorous, carefully controlled PET investigations with quantified motor and cognitive behavioral measures.